Hepatic energy state is regulated by glucagon receptor signaling in mice

Eric D. Berglund, Robert S. Lee-Young, Daniel G. Lustig, Sara E. Lynes, E. Patrick Donahue, Raul C. Camacho, M. Elizabeth Meredith, Mark A. Magnuson, Maureen J. Charron, David H. Wasserman

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor-null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism.

Original languageEnglish (US)
Pages (from-to)2412-2422
Number of pages11
JournalJournal of Clinical Investigation
Volume119
Issue number8
DOIs
StatePublished - Aug 3 2009

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Glucagon Receptors
Glucagon
Liver
Physiological Stress
Inbred C57BL Mouse
Fasting
Phosphoenolpyruvate
AMP-Activated Protein Kinases
Glucose Clamp Technique
Adenine Nucleotides
Metabolic Diseases
Metabolic Networks and Pathways
Hypoglycemia
Hormones
Insulin
Glucose

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Berglund, E. D., Lee-Young, R. S., Lustig, D. G., Lynes, S. E., Donahue, E. P., Camacho, R. C., ... Wasserman, D. H. (2009). Hepatic energy state is regulated by glucagon receptor signaling in mice. Journal of Clinical Investigation, 119(8), 2412-2422. https://doi.org/10.1172/JCI38650

Hepatic energy state is regulated by glucagon receptor signaling in mice. / Berglund, Eric D.; Lee-Young, Robert S.; Lustig, Daniel G.; Lynes, Sara E.; Donahue, E. Patrick; Camacho, Raul C.; Meredith, M. Elizabeth; Magnuson, Mark A.; Charron, Maureen J.; Wasserman, David H.

In: Journal of Clinical Investigation, Vol. 119, No. 8, 03.08.2009, p. 2412-2422.

Research output: Contribution to journalArticle

Berglund, ED, Lee-Young, RS, Lustig, DG, Lynes, SE, Donahue, EP, Camacho, RC, Meredith, ME, Magnuson, MA, Charron, MJ & Wasserman, DH 2009, 'Hepatic energy state is regulated by glucagon receptor signaling in mice', Journal of Clinical Investigation, vol. 119, no. 8, pp. 2412-2422. https://doi.org/10.1172/JCI38650
Berglund ED, Lee-Young RS, Lustig DG, Lynes SE, Donahue EP, Camacho RC et al. Hepatic energy state is regulated by glucagon receptor signaling in mice. Journal of Clinical Investigation. 2009 Aug 3;119(8):2412-2422. https://doi.org/10.1172/JCI38650
Berglund, Eric D. ; Lee-Young, Robert S. ; Lustig, Daniel G. ; Lynes, Sara E. ; Donahue, E. Patrick ; Camacho, Raul C. ; Meredith, M. Elizabeth ; Magnuson, Mark A. ; Charron, Maureen J. ; Wasserman, David H. / Hepatic energy state is regulated by glucagon receptor signaling in mice. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 8. pp. 2412-2422.
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